Method for reducing side effects of aminoglycoside antibiotics

ABSTRACT

Side effects of an aminoglycoside antibiotic, renal toxicity and 8th nerve toxicity are reduced by using said aminoglycoside antibiotic in combination with 2,5-di-0-acetyl-D-glycosaccharo1,4: 6,3-dilactone.

United States Patent Furuno et al.

METHOD FOR REDUCING SIDE EFFECTS OF AMINOGLYCOSIDE ANTIBIOTICS Inventors: Kouji F uruno; Hideki Nakano;

Syuzo Matsubara; Akitoshi Shioya, all of Tokyo, Japan Chugai Seiyaku Kabushiki Kaisha, Tokyo, Japan Filed: Aug. 7, 1974 Appl. No.: 495,498

Assignee:

Foreign Application Priority Data Aug. 31, 1973 Japan 48-97344 US. Cl 424/180; 424/279 Int. Cl. A01N 9/00; AOlN 9/28 Field of Search 424/279, 180

[ Dec. 23, 1975 References Cited OTHER PUBLlCATIONS Chemical Abstract 67:102793m (1967). Physicians Desk Reference, 27 Ed., 1256-1259.

Primary Examiner-Jerome D. Goldberg Assistant ExaminerD. W. Robinson Attorney, Agent, or Firm-Browdy and Neimark [5 7] ABSTRACT 9 Claims, No Drawings METHOD FOR REDUCING s nitfiirtsfim l AMINOGLY C OSIDE"ANTIBIOTICS; r r The present inventionrela tes to a method for.reducing the side effects of an aminoglycoside antibiotic I g acid addition salt, sulfuric acid addition salt etc.

when administered to mammals including human beings and poultry. i

The term aminoglycoside antibiotic isa general term for-an antibiotic 'having irtits 'moleculedeoxystreptamine structure to which arninp sugariis bonded by glycoside bond. The antibiotic has so-strong inhibitory effects on grampositive and -negative bacteria, acid fast bacteria etc; that itis regarded as an important antibiotic in view of practical uses,-

The antibiotics exhibit a broad anti-bacterial spec-f trum in vitro, can control the,p r oliferati onof various pathogenic bacteria even at' a very low 'concentration and. also exhibit an excellent .prophylactic activity against experimental infection of various pathogenic bacteria in mice. The antibiotics however;exhibit 8th nerve and renal toxicities and their application has been limited. Particularly renal toxicity is regarded as a serious problem and jtglS known according to statistical study of indexes indicating renal/functionsthat renal functions become worse as the cumulative dose of the antibiotic, even Kanamycin A which has the lowest toxicity among this series of antibiotics, increases. Further, the antibiotic has never been administered to a patient having renal function disorder or to be given various plasma expanders, since serious or fatal disorder of renal function is often observed in such cases.

It is an object of the present invention to provide a method for reducing side effects of an aminoglycoside antibiotic when administered to mammals including human beings and poultry.

According to the present invention, side effects of an aminoglycoside antibiotic can be reduced by the administration of aminoglycoside antibiotic in combination with the oral administration of at least 50% by weight of 2,5-di-O-acetyl-D-gluco-sacchro-l,4: 6,3- dilactone based on the free form of said aminoglycoside antibiotic to mammals and poultry.

Aminoglycoside antibiotics used in the present invention include Streptomycin, Neomycin B and C, Kanamycin A, B and C, Ribostamycin, Paromomycin l and Il, Gentamicin complex, Tobramycin, Butirosin A and B, Lividomycin A and B, 3',4'-dideoxykanamycin B,

. The aminoglycoside. antibiotic'may be either free ;base,or mineral acidaddition salt 'such as hydrochloric r The; lower. limit of dose or 2, 5-di-O-acetyl-D- glucosaccharo-lA: 6,3-dilactone in view of side effects-reducing e ffect is 50%,by weight based on the free form of an aminoglycosidel.antibiotic, while the upper 10 limit is notcritical becauseof the very low toxicity of 2,5 di-O-acetyl-D-glucosaccharo'1,4: 6,3-dilactone. In general it is preferable to use 100 l00 0% by weight of said'compound basedfihonfthe free, form of an aminoglycoside antibiotic.

Geneially aminoglycoside"antibiotics are administered by intramuscular injction.5ln such'cases appearance of renal toxicity -is aprobleni; 2,5-di-0-ace'tyl-D- glucosaccharol ,4: 6,3-dilactone is orally administered simultaneously with or just prior to the administration '20 of an aminoglycoside antibiotic. Preferably the former compound is further administered every 6 hours after the initial administration, since the half-life of excre- ,tion, of glucosaccharic acid into urine is 2 3 hours.

. The-method for reducing side effects of aminoglycoside antibiotic of the present invention can be applied to any animal which is to be administered with aminoglycoside antibiotics, for example, human beings, monkeys, horses, bovines, dogs, cats, chickens, pigs, sheep.

The following example illustrates the present invention but is not intended to limit the scope of the present invention.

EXAMPLE The Wister-Imamichi strain male rats (weighing 250 300g) were used as test animals by dividing them into groups of 5 rats each.

After 48 hours of abstinence from water, each rat was orally administered with 300mg/kg of 2,5-di-O- acetyl-D-glucosaccharo-l ,4: 6,3-dilactone, and 10 minutes after the administration, the rat was intramuscuused as control.

The results are shown in the following table:

Sismomicin, l-N-[(S)-4-amino-2-hydroxybutyryl1-3',- 4'-dideoxykanamycin B, l-N-[(S)-4-arnino-2-hydrox- Antibiotics (dose) Group Percentage of Urea-nitrogen Occult blood (weight of the free renal edema Content in blood in urine form (mg)/kg) (mg/dl) Kanamycin A (300) administered 0.70 25 control 0.92 Kanamycin B (200) administered 0.78 35 control 0.98 -H+ Neomycin (75) administered 0.79 35 2 control Ll 5 -H+ Streptomycin (150) administered 0.71 27 control 0.8] 60 +-H- Ribostamycin (400) administered 0.73 25 control 0.99 95 +H- Paromomycin (200) administered 0.75 30 control I .06 I50 Gentamicin (50) administered 0.73 25 control 0.82 60 +H- "(Renal weight/body weight) X l00 'Mealured with the use of test papers for measuring urea-nitrogen content in blood manufactured by Ono Yakuhin.

What is claimed is:

l. A method of reducing the renal toxicity and 8th nerve toxicity to mammals or poultry of aminoglyco- 3 side antibiotic comprising administering said aminoglycoside antibiotic in combination with the oral administration of 2,5-di-O-acetyl-D-glucosaccharo-l,4: 6,3-dilactone to said mammals or poultry for treating bacterial infection in an amount of 50-l000%- by weight based on the free form of said antibiotic. V

2. The method of claim 1 wherein said aminoglycoside antibiotic is Streptomycin, Neomycin B and C,

Kanamycin A, B and C, Ribostamycin, Paromomycin l 4 dideoxyneamine, or l-N-[(S)-4-amino-2-hydroxybutyryl]kanamycin A.

4. The method of claim 3 wherein said mineral acid addition salt is the sulfuric acid addition salt or hydrochloric acid addition salt.

5. Themethod of claim 1 wherein said mammal is a human being.

6. The method of claim 1 wherein said mammals and poultry are monkeys, horses, bovines, dogs, cats, chickens,,pigs or sheep.

7. The method of claim 1 wherein said 2,5-di-O-acetyl-D-glucosaccharo-l,4: 6,3-dilactone is used in an amount of 100 1000% by weight based on the free form of the aminoglycoside antibiotic.

8. The method of claim 1 characterized in that, every six hours after initially administering 2,5-di-O-acetyl- 'D-glucosaccharol,4: 6,3-dilactone in an amount of about 50% by weight based on the free form of the aminoglycoside antibiotic simultaneously with or prior to the administration of the aminoglycoside antibiotic, the same dosage of 2,5-di-O-acetyl-D-glucosaccharo- 1,4: 6,3-dilactone is further administered.

9. The method of claim 1, wherein said aminoglycoside antibiotic is gentamicin.

III 

1. A METHOD OF REDUCING THE RENAL TOXICITY AND 8TH NERVE TOXICITY TO MAMMALS OR POULTRY OF AMMIONOGLYCOSIDE ANTIBIOTIC COMPRISING ADMINISTERING SAID AMMINOGLYCOSIDE ANTIBIOTIC IN COMBINATION WITH THE ORAL ADMINISTRATION OF 2,5-DI-O-ACETYLD-GLUCOSACCHARO-1,4:6,3-DILACTONE TO SAID MAMMALS OR POULTRY FOR TREATING BACTERIAL INFECTION IN AN AMOUNT OF 50-1000%BY WEIGHT BASED ON THE FREE FORM OF SAID ANTIBIOTIC.
 2. The method of claim 1 wherein said aminoglycoside antibiotic is Streptomycin, Neomycin B and C, Kanamycin A, B and C, Ribostamycin, Paromomycin I and II, Gentamicin complex, Tobramycin, Butirosin A and B, Lividomycin A and B, 3'',4''-dideoxykanamycin B, Sismomicin, 1-N-((S)-4-amino-2-hydroxybutyryl)-3'',4''-dideoxykanamycin B, 1*-N((S)-4-amino-2-hydroxybutyryl)-3'',4''-dideoxyneAmine, or 1-N-((S)-4-amino-2-hydroxybutyryl)kanamycin A.
 3. The method of claim 1 wherein said aminoglycoside antibiotic is a mineral acid addition salt of Streptomycin, Neomycin B and C, Kanamycin A, B and C, Ribostamycin, Paromomycin I and II, Gentamicin complex, Tobramycin, Butirosin A and B, Lividomycin A and B, 3'',4''-dideoxykanamycin B, Sismomicin, 1-N-((S)-4-amino-2-hydroxybutyryl)-3'',4''-dideoxykanamycin B, 1-N-((S)-4-amino-2-hydroxybutyryl)-3'',4''-dideoxyneamine, or 1-N-((S)-4-amino-2-hydroxybutyryl)kanamycin A.
 4. The method of claim 3 wherein said mineral acid addition salt is the sulfuric acid addition salt or hydrochloric acid addition salt.
 5. The method of claim 1 wherein said mammal is a human being.
 6. The method of claim 1 wherein said mammals and poultry are monkeys, horses, bovines, dogs, cats, chickens, pigs or sheep.
 7. The method of claim 1 wherein said 2,5-di-O-acetyl-D-glucosaccharo-1,4: 6,3-dilactone is used in an amount of 100 -1000% by weight based on the free form of the aminoglycoside antibiotic.
 8. The method of claim 1 characterized in that, every six hours after initially administering 2,5-di-O-acetyl-D-glucosaccharo-1, 4: 6,3-dilactone in an amount of about 50% by weight based on the free form of the aminoglycoside antibiotic simultaneously with or prior to the administration of the aminoglycoside antibiotic, the same dosage of 2,5-di-O-acetyl-D-glucosaccharo-1,4: 6,3-dilactone is further administered.
 9. The method of claim 1, wherein said aminoglycoside antibiotic is gentamicin. 